Project Abstract Our preliminary studies have identified the receptor for advanced glycation end-products (RAGE) as a smoke- induced pattern recognition receptor with potent pro-inflammatory characteristics. Specific research demonstrated that RAGE is increased in the lung following first and secondhand smoke exposure and that transgenic mice that conditionally up-regulate RAGE manifest characteristics of a smoker?s lung in the absence of smoke. Exposure to tobacco smoke is the major cause of chronic obstructive pulmonary disease (COPD), the third leading cause of death, and it is characterized by debilitating inflammation and deleterious respiratory tissue loss. SAGEs are semi- synthetic glycosaminoglycan ethers that are potent modulators of inflammation in numerous animal models of human disease, and are in preclinical development for periodontitis, oral mucositis, and bladder inflammation. Importantly, SAGEs significantly inhibit interactions between RAGE and its many ligands necessary for signaling. The present proposal is the first to thoroughly assess the biology of RAGE signaling in the context of first and secondhand smoke exposure. A key innovation of this proposal is a collection of animal models that tightly control RAGE expression including RAGE null mice, tissue-specific transgenic mice that up-regulate RAGE, and mice harboring phosphorylation deficient RAGE alleles. This proposal also has significant impact due to its clinical potential to ameliorate smoke-induced inflammation and remodeling. The central hypothesis is that RAGE expression by pulmonary epithelium induces COPD by orchestrating widespread inflammation and parenchymal tissue loss. We further hypothesize that SAGEs inhibit RAGE-ligand signaling and potentially modify the course of tobacco-mediated disease via RAGE targeting. Two specific aims are proposed, and each uses advanced molecular methodologies employed by undergraduate students to test these hypotheses. The studies outlined in this proposal will validate RAGE signaling as a target pathway for the prevention or attenuation of COPD in individuals unable or unwilling to remove smoke exposure but may also help to clarify RAGE-mediated pathogenesis in a number of physiological processes.